Intermediate for preparing a catechol-O-methyltransferase inhibitor

Abstract

There is disclosed a methylated intermediate which may be demethylated to provide an inhibitor of catechol-O-methyltransferase useful in the treatment of Parkinson's disease. Also disclosed are methods of making and using said intermediate.

The invention claimed is: 
     
       1. A compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       2. A compound as claimed in  claim 1  in crystalline form. 
     
     
       3. A compound as claimed in  claim 1  in an organic solvent. 
     
     
       4. A compound as claimed in  claims 3  wherein the organic solvent is N-methyl pyrrolidone. 
     
     
       5. A method of preparing a compound of the formula (II) 
       
         
           
           
               
               
           
         
       
       or a salt thereof which comprises O-demethylation of a compound of the formula (I) as set forth in  claim 1  or a salt thereof. 
     
     
       6. A method as claimed in  claim 5  wherein the demethylation is effected by reaction with a Lewis acid and a base. 
     
     
       7. A method as claimed in  claim 6  wherein the demethylation is carried out in solution in N-methyl pyrrolidone. 
     
     
       8. A method as claimed in  claim 5  performed at 45° C. to 70° C. 
     
     
       9. A method as claimed in  claim 5  wherein the compound of formula (I) or salt thereof is prepared by the oxidation of a compound of formula (III) 
       
         
           
           
               
               
           
         
       
       or salt thereof. 
     
     
       10. A method as claimed in  claim 9  wherein the oxidizing agent is H 2 O 2 . 
     
     
       11. A method as claimed in  claim 10  wherein the H 2 O 2  is H 2 O 2 -urea addition complex. 
     
     
       12. A method as claimed in  claim 10  carried out in solution in methylene chloride to the presence of trifluoroacetic anhydride. 
     
     
       13. A method as claimed in  claim 9  wherein the compound of the formula (III) is prepared by the reaction of the compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein Y is a halo group or OR, in which R is hydrogen or a C1-C6 alkyl, 
       with a compound of formula (V) 
       
         
           
           
               
               
           
         
       
     
     
       14. A method as claimed in  claim 13  wherein Y is chloro and the compound of the formula (IV) has the formula (VIII): 
       
         
           
           
               
               
           
         
       
     
     
       15. A method as claimed in  claim 13  wherein Y is OR and R is hydrogen and the compound of formula (IV) has formula (VI): 
       
         
           
           
               
               
           
         
       
     
     
       16. A method as claimed in  claim 15 , wherein the reaction includes the addition of a coupling reagent. 
     
     
       17. A method as claimed in  claim 13  wherein the reaction of the compounds of formula (V) and formula (IV) takes place in a mixture of dimethylacetamide, tetrahydrofuran pyridine, or in dioxane in presence of pyridine. 
     
     
       18. A method as claimed in  claim 17  wherein the reaction is performed at a temperature of 100° C. to 120° C. 
     
     
       19. A method as claimed in  claim 13  wherein, following reaction of the compounds of formula (IV) and formula (V), ethanol is added to the mixture. 
     
     
       20. A method as claimed in  claim 9  wherein the compound of formula (III) is oxidized to the compound of formula (I) without isolation or purification following the reaction of compounds of formula (IV) and formula (V). 
     
     
       21. A method as claimed in  claim 9  wherein the compound of formula (I) is crystallised from an organic solvent. 
     
     
       22. A method as claimed in  claim 21  wherein the organic solvent is a mixture of toluene and formic acid. 
     
     
       23. A method as claimed in  claim 9  wherein the compound of formula (II) is crystallised from an organic solvent. 
     
     
       24. A method as claimed in  claim 23  wherein the solvent is a mixture of propan-2-ol and formic acid. 
     
     
       25. A method as claimed in  claim 9  wherein the compound of formula (VIII) is prepared from the compound of the formula (VI) 
       
         
           
           
               
               
           
         
       
       by reaction with SOCl 2  in dioxane at 75° C. to 85° C. or with SOCl 2  in DCM with DMF as catalyst. 
     
     
       26. A method as claimed in  claim 25  wherein the compound of formula (VI) was prepared by the nitration of vanillic acid with 65% HNO 3  in acetic acid or by the nitration of methyl vanillate with 65% HNO 3  in dioxane/water, followed by the hydrolysis with sodium hydroxide. 
     
     
       27. A method as claimed in  claim 9  wherein the compound of formula (V) is prepared from the compound of the formula (VII) 
       
         
           
           
               
               
           
         
       
       by reaction with hydroxylamine in the presence of 1,10-phenanthroline monohydrate. 
     
     
       28. A method as claimed in  claim 27  wherein the reaction is carried in a mixture of methanol and water at 70-80° C. 
     
     
       29. A method as claimed in  claim 6  wherein the demethylation is effected by reaction with aluminium chloride and pyridine. 
     
     
       30. A method as claimed in  claim 13  wherein Y is chloro or OR, in which R is hydrogen, methyl or ethyl.